Synthesis of analogs of (1,4)-3- and 5-imino oxazepane, thiazepane, and diazepane as inhibitors of nitric oxide synthases.

A series of 3- and 5-imino analogs from oxazepane, thiazepane, and diazepane was prepared and evaluated as inhibitors of human nitric oxide synthesis (NOS). The most potent iNOS inhibitor was the thiazepane analog 25 (IC(50) = 0.19 microM).

Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase.

Syntheses and evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase (NOS) are discussed. An extensive SAR was established for pyrrolidin-2-imines class of compounds. The amidines came out as the most potent inhibitors in addition to displaying selectivity.

Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor.

Efforts toward the exploration of the title compounds as CCR5 antagonists are disclosed. The basis for such work stems from the fact that cellular proliferation of HIV-1 requires the cooperative assistance of both CCR5 and CD4 receptors. The synthesis and SAR of pyrrolidineacetic acid derivatives as CCR5 antagonists displaying potent binding and antiviral properties in a HeLa cell-based HIV-1 infectivity assay are discussed.

Syntheses and biological evaluation of 5-(piperidin-1-yl)-3-phenyl-pentylsulfones as CCR5 antagonists.

Cellular proliferation of HIV-1 requires the cooperative assistance of both the CCR5 and CD4 receptors. Our medicinal chemistry efforts in this area have resulted in the identification of N-alkyl piperidine sulfones as CCR5 antagonists. These compounds display potent binding and show antiviral properties in HIV-1 spread cell-based assays.

Retroperitoneal perforation in ulcerative colitis with mediastinal and subcutaneous emphysema.

Retroperitoneal colonic perforation in patients with ulcerative colitis is rare. We report such a case in a patient with severe ulcerative colitis without toxic dilatation in whom mediastinal and subcutaneous emphysema also developed. Unlike previously reported cases, our patient was treated conservatively with intravenous fluids, parenteral nutrition, intravenous hydrocortisone, and antibiotics. After 2 weeks, the mediastinal and subcutaneous emphysema and the retroperitoneal air completely disappeared.

Relationship of serum gastrin and Helicobacter pylori in the gastric antral and body mucosa.

OBJECTIVE: To evaluate the relationship between serum gastrin and Helicobacter pylori status in the antrum and body of gastric mucosa. METHODS: Fasting and post-meal serum gastrin level were studied by radioimmunoassay in 41 patients with dyspepsia. These patients were divided into three groups depending on H pylori status ie H pylori present in both antrum and body; (A+B+; n = 13), present in antrum but not in the body; (A+B-; n = 7) and absent in both antrum and body A-B-; n = 21. RESULTS: There was no difference in fasting or post meal serum gastrin levels between the groups A+B+ and A+B-. Serum gastrin values 20 and 40 minutes post meal were significantly higher (p < 0.05) in the group A+B+ as compared to A+B-. CONCLUSION: Post meal serum gastrin levels are higher in patients with dyspepsia in whom Helicobacter pylori is present in the antral and body mucosa as compared to those in whom it is present in the antrum only.

In vivo evaluation of three acid-stable azalide compounds, L-701,677, L-708,299 and L-708,365 compared to erythromycin, azithromycin and clarithromycin.

L-701,677, L-708,299 and L-708,365 are novel azalide derivatives of erythromycin that exhibit improved acid stability over erythromycin, azithromycin and clarithromycin. The half-life in aqueous solution at pH = 2.1 of these compounds ranged from 0.3 hour for erythromycin to 16.2 hours for L-708,299. The rank order of half-life in acid solution from most to least stable was L-708,299 > L-701,677 > L-708,365 > azithromycin = clarithromycin > erythromycin. In a disseminated Streptococcus pyogenes mouse infection model, azithromycin and L-708,365 were slightly more efficacious than clarithromycin, L-701,677 and L-708,299; all 5 compounds being more active than erythromycin. In a Klebsiella pneumoniae pulmonary challenge mouse model, azithromycin, L-701,677, L-708,299 and L-708,365 were all equal in efficacy and at least four-fold more active than clarithromycin and erythromycin. Clarithromycin, L-708,365 and interestingly erythromycin, showed greater bacterial clearance than azithromycin, L-701,677 and L-708,299 in a localized infection model that measured clearance of Staphylococcus aureus from mouse thigh tissues. Our results indicate that L-701,677, L-708,299 and L-708,365 exhibit improved acid stability and were at least equally efficacious as presently marketed macrolide/azalide antibiotics.

Helicobacter pylori in dental plaque.

Human and animal stomachs were considered the only reservoirs of Helicobacter pylori until it was identified in human dental plaque (DP). H. pylori is infrequent in populations from developed countries, but is widespread in those from developing countries. The failure of triple drug therapy to clear H. pylori from DP, despite its clearance from gastric mucosa, raised the possibility of DP as a permanent reservoir of H. pylori and a potential source of reinfection of gastric mucosa. Attempts should be made to eradicate H. pylori both from the gastric mucosa and from DP to ensure a permanent cure of duodenal ulcer. Unfortunately, all attempts to eradicate H. pylori from DP have failed.

Relationship of serum gastrin and Helicobacter pylori in the gastric antral and body mucosa.

OBJECTIVE: To evaluate the relationship between serum gastrin and Helicobacter pylori status in the antrum and body of gastric mucosa. METHODS: Fasting and post-meal serum gastrin levels were studied by radioimmunoassay in 41 patients with dyspepsia. These patients were divided into three groups depending on H pylori status ie H pylori present in both antrum and body; (A + B+; n = 13), present in antrum but not in the body; (A + B-; n = 7) and absent in both antrum and body; (A - B-; n = 21). RESULTS: There was no difference in fasting or post meal serum gastrin levels between the groups A + B+ and A - B-. Serum gastrin values 20 and 40 minutes post meal were significantly higher (p < 0.05) in the group A + B+ as compared to A + B-. CONCLUSION: Post meal serum gastrin levels are higher in patients with dyspepsia in whom Helicobacter pylori is present in the antral and body mucosa as compared to those in whom it is present in the antrum only.

Helicobacter pylori in dental plaque of children and their family members.

A prospective study was undertaken to determine the presence of Helicobacter pylori in the dental plaque of children and their family members. 22 children (age range: 2-12 years; males: 16) admitted to the paediatric ward for various disorders and 17 healthy family members (age range: 7-40 years; males: 9) of 13 of these children were screened for presence of Helicobacter pylori in the dental plaque by the rapid urease test. H. pylori was detected in dental plaque of 82% (18/22) children and 88% (15/17) of family members. In 85% (28/33) of the positive cases the rapid urease test was positive within 1 hour. Our observations indicate that Helicobacter pylori is present in the dental plaque of majority of children and their family members.

Age-related prevalence of Helicobacter pylori antibodies in Indian subjects.

OBJECTIVE: To determine the age-related prevalence of Helicobacter pylori antibodies in Indian subjects without upper gastrointestinal symptoms. MATERIAL AND METHODS: Sera of 340 subjects without any upper gastrointestinal complaints were screened for IgG and IgA Helicobacter pylori antibodies by the ELISA technique. RESULTS: The prevalence of IgG and IgA antibodies was 22%, 56% and 87% and 48%, 58% and 83% in 0-4, 5-9 and 10-19 year age groups respectively; thereafter it remained almost constant upto fifth decade. A significant fall in IgG and IgA prevalence was observed from fifth to seventh decades. CONCLUSION: Our data indicate that in India exposure to Helicobacter pylori occurs early in life and is widespread; about 83% of the population is exposed to Helicobacter pylori during the first two decades of life. The comparable prevalence rates of IgG antibodies to Helicobacter pylori and hepatitis A virus, in different age groups, in India and in the West, suggest a feco-oral mode of transmission for Helicobacter pylori.

Wilson's disease: varied hepatic presentations.

BACKGROUND: Wilson's disease is an inherited disorder of copper metabolism. Previous Indian studies have high-lighted the neurological manifestations of this disorder. Eleven patients with Wilson's disease with different hepatic manifestations are reported. METHODS: Patients referred to the gastroenterology department of a tertiary referral center were investigated for Wilson's disease, based on clinical suspicion, with slit-lamp examination for Kayser-Fleischer rings, serum ceruloplasmin and 24-hour urinary copper estimation. Liver biopsy was done whenever possible. RESULTS: Patients with Wilson's disease presented as acute viral hepatitis (n = 5), fulminant hepatic failure (n = 2), subacute hepatic failure (n = 2) and cryptogenic cirrhosis (n = 2). Therapy with penicillamine/trientene and zinc sulphate was started in 9 patients; 5 showed good response to therapy, one had to be switched to trientene due to penicillamine toxicity, two died, and one was lost to follow-up. CONCLUSION: Wilson's disease has varied hepatic presentations and should be suspected in all patients with unexplained liver disease. Any young adult presenting with acute hepatitis or fulminant hepatic failure who has evidence of underlying chronic liver disease or associated hemolytic anemia should be investigated for Wilson's disease. Therapy with penicillamine or trientene combined with zinc sulphate shows improvement in a majority of patients.

Congestive gastropathy: factors influencing development, endoscopic features, Helicobacter pylori infection, and microvessel changes.

OBJECTIVES: To study 1) the factors influencing the development of congestive gastropathy (CG) in patients with portal hypertension (PHT), 2) the changes in gastric microvessels in patients with PHT with and without CG, and 3) to determine whether Helicobacter pylori plays any role in the pathogenesis of CG. METHODS: One hundred eighteen patients with PHT (102 cirrhosis, 16 noncirrhotic portal fibrosis) were evaluated by videogastroscopic examination. Antral biopsy tissue was examined for microvessel changes, histological gastritis, and H. pylori infection in 85 of 118 patients and 45 controls. Portal venous pressure (PVP) was determined by hepatic venous pressure gradient in 17 patients with CG. RESULTS: CG was present in 71 (60%) patients with PHT, of whom 41 (58%) had mild and 30 (42%) had severe CG. CG was observed with equal frequency in cirrhosis (63%) and noncirrhotic portal fibrosis (44%). The incidence of CG was higher in patients with severe liver disease, a past history of hemetemesis, in those with esophageal varices, and in those with gastric varices. Severe CG was commonly observed in patients with large size esophageal varices and in those with gastric varices. There was significant dilation of gastric mucosal vessels in patients with PHT, but in this regard there was no significant difference between patients with and without CG. The presence of H. pylori, histological gastritis, degree of PVP, or degree of capillary dilation did not influence the severity of CG. CONCLUSIONS: CG occurs commonly in patients with PHT, especially those with severe liver disease, past history of hemetemesis, and esophagogastric varices. Patients with PHT have significant gastric microvessel changes. The severity of CG appears to be independent of PVP, capillary dilation, H. pylori infection, or histological gastritis.

Electron microscopic observations in gastric mucosa of habitual tobacco chewers.

Clinical evaluation, upper gastrointestinal endoscopy and electron microscopy of mucosal biopsies from antrum, body and fundus of stomach were performed in three control subjects and 17 habitual tobacco chewers. Electron microscopic abnormalities such as discontinuous, fragmented basement membrane with reduction in hemidesmosomes, and widened intercellular spaces filled with clusters of desmosomes were found in the gastric mucosa of habitual tobacco chewers; these were similar to those reported in experimental carcinogenesis and leukoplakia. It is concluded that habitual chewing of tobacco produces electron microscopic alterations in the human gastric mucosa which may be important precursors for gastric malignancy.

Genetic hemochromatosis presenting as asymptomatic hepatomegaly.

A case of genetic hemochromatosis presented with asymptomatic hepatomegaly. The diagnosis was based on elevated serum iron, serum ferritin and transferrin saturation, a characteristic picture on magnetic resonance imaging, and liver biopsy showing cirrhosis with excessive iron deposits in the liver parenchyma. The extreme rarity of this disease in our country is perhaps determined by hereditary factors.

Helicobacter pylori and acid secretion.

BACKGROUND: Helicobacter pylori has been implicated in the aetiopathogenesis of peptic ulcer but data on the effect of infection by this organism on gastric acid secretion are equivocal. We, therefore, examined the effect of the presence of Helicobacter pylori in the antrum and body of the stomach on acid secretion. METHODS: We used the augmented histamine test and intragastric titration in three groups of patients. In one group Helicobacter pylori was present in both the antrum and body of the stomach, in the second it was present in the antrum but not the body, and in the third the organism was absent. RESULTS: There were no significant differences in acid secretion between these three groups. CONCLUSION: The presence of Helicobacter pylori in the mucosa of the gastric antrum and body has no effect on acid secretion.